Cough/cold mixtures comprising non-steroidal anti-inflammatory drugs

ABSTRACT

Pharmaceutical compositions and methods of using same comprising a non-steroidal anti-inflammatory drug in combination with at least one other active component selected from an anti-histamine, decongestant, cough suppressant (antitussive) or expectorant are provided for the relief of cough, cold and cold-like symptoms.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 887,205, filedJuly 21, 1986, now U.S. Pat. No. 4,738,966, which is a divisionalapplication of Ser. No. 752,546, filed July 8, 1985, now U.S. Pat. No.4,619,934, which is a divisional application of Ser. No. 598,502, filedApr. 9, 1984, now U.S. Pat. No. 4,552,899. Other related divisionalapplications include Ser. No. 016,333, filed Feb. 19, 1987, now U.S.Pat. No. 4,749,697; Ser. No. 016,376, filed Feb. 19, 1987, now U.S. Pat.No. 4,749,022; Ser. No. 016,377, filed Feb. 19, 1987, now U.S. Pat. No.4,749,711; Ser. No. 016,396, filed Feb. 19, 1987, now U.S. Pat. No.4,749,723; Ser. No. 016,397, filed Feb. 19, 1987, now U.S. Pat. No.4,749,720; Ser. No. 172,973, filed Mar. 22, 1988, which is acontinuation of Ser. No. 016,398, filed Feb. 19, 1987; and Ser. No.016,563, filed Feb. 19, 1987, now U.S. Pat. No. 4,749,721.

BACKGROUND OF THE INVENTION

The present invention relates generally to novel pharmaceuticalcompositions of matter comprising one or more non-steroidalanti-inflammatory drugs (NSAID) in combination with at least oneantihistamine, sympathomimetic drug (nasal decongestant, bronchodilator)cough suppressant and/or expectorant, optionally in combination withsuitable pharmaceutically acceptable non-toxic carriers or excipients,and to methods of using said compositions in the treatment, managementor mitigation of cough, cold, cold-like and/or flue symptoms and thediscomfort, pain, fever and general malaise associated therewith.

Non-narcotic analgesics, most of which are also known as non-steroidalanti-inflammatory drugs (NSAID), are widely administered orally in thetreatment of mild to severe pain. Within this class, the compounds varywidely in their chemical structure and in their biological profiles asanalgesics, anti-inflammatory agents and antipyretic agents. Among themost commonly used members of the non-narcotic analgesic class of drugsare aspirin, acetaminophen and phenacetin. Aspirin and acetaminophenhave heretofore been included as the pain reliever and fever-reducingcomponent in conventional cough/cold multi-symptom alleviatingcompositions.

However, a number of alternative non-narcotic agents offering a varietyof advantages over these conventionally employed non-narcotic analgesicantipyretics have now been developed. The principal advantages of thesenon-steroidal anti-inflammatory drugs include not only the clinicallysuperior analgesic, anti-flammatory and antipyretic activity of theseagents compared to aspirin, acetaminophen or phenacetin, but also aminimization of the adverse side affects experienced with theseconventional agents; more specifically, the gastrointestinal ulcerationsexperinced with aspirin and the hepatic toxicity prevalent with thechronic use of acetaminophen.

Exemplary prior art cough/cold formalations containing aspirin oracetaminophen include Coricidin®, Coricidin D®, Comtrex®, Dristan®,Daycare®, Cotylenol®, Sinubid®and the like. These formulations generallycontain in addition to aspirin or acetaminophen, one or moreantihistaminics, decongestants, cough suppressants, antitussives andexpectorants.

While aspirin and acetaminophen have been utilized in these previouscompositions, it has not been heretofore proposed to use any of thenewer non-steroidal anti-inflammatory drugs (i.e., excluding aspirin,acetaminophen and phenacetin) in the preparation of advantageouscough/cold pharmaceutical compositions.

SUMMARY OF THE INVENTION

It is, therefore, a primary object of the present invention to providepharmaceutical compositions of matter comprising an analgesicallyeffective amount of a non-steroidal anti-inflammatory drug (NSAID) incombination with at least one of an antihistamine, decongestant, coughsuppressant, expectorant and, optionally, including pharmaceuticallyacceptable carriers therefor.

It is further object of the present invention to provide methods for thesymptomatic relief of cough, cold cold-like and flu symptoms by theadministration of preselected dosages of the pharmaceutical compositionsof the present invention. Cold-like symptoms are used herein refers tocoryza, nasal congestion, upper respiratory infections, allergicrhinitis, otitis, sinusitis, etc.

Another object of the present invention is to provide suitable dosageunit forms of one or more NSAID's in combination with at least one ofthe aforementioned antihistamines, decongestants, etc. adapted forconvenient oral administration.

DETAILED DESCRIPTION OF THE INVENTION

More specifically, the applicants herein have found that certainnon-steroidal anti-inflammatory agents are ideally suited for use incough/cold formulations by reason of their enhanced analgesicanti-inflammatory and antipyretic activity and low incidence of untowardside effects, particularly at the optimum dosages provided for in thepresent invention, compared to aspirin or acetaminophen.

The superiority of various of the non-narcotic analgesics belonging tothe non-steroidal anti-inflammatory drug class in comparative studieswith aspirin and acetaminophen is well documented in the literature.

Cooper in 1977 found that ibuprofen 400 mg had a greater peak effect andlonger duration of action than aspirin 650 mg. Copper, S.A., Needle,A.E., Kruger, G.O. 1977. "An Analgesic Relative Potency Assay ComparingAspirin, Ibuprofen and Placebo. " J. Oral Surg. 35:898-903. Cooper inanother study in 1982 found 400 mg of ibuprofen to be more effectivethan aspirin 650 mg. Cooper, S.A., Engel, J., Ladov, M., Precheur, H.,Rosenheck, A., Rauch, D. 1982. "Analgesic Efficacy of anIbuprofen-codeine Combination." Pharmocotherapy 2:162-67. Sunshine et alfound ibuprofen to be significantly superior to aspirin in the relief ofpost-episiotomy pain. Sunshine, A. et al, Clinical Pharmacology andTherapeutics, :24:254-250, 1983.

Dionne in 1982 found ibuprofen to be more effective than acetaminophenin delaying the onset and intensity of post-operative dental pain.Dionne, R.A., Campbell, R.A., Cooper, S.A., Hall, D.L., Buckingham, B."Suppression of Post operative Pain by Preoperative Administration ofIbuprofen in Comparison to Placebo, Acetaminophen and Acetaminophen PlusCodeine." J. Clin. Phamacol. (In press).

Naproxen sodium 550 mg was compared with 650 mg of aspirin and was foundto provide earlier and better pain relief than aspirin by Sevelius, H.,J. Clin. Pharmacol. 20:480-485, 1980. "Comparative Analgesic Effects ofNaproxen Sodium, Aspirin and Placebo."

Flurbiprofen 50 and 100 mg was significantly more effective than aspirin600 mg. Flurbiprofen 25 mg was slightly less effective than aspirin 600mg. Sunshine, A., Olson N.Z., Laska, E.M. Zighelboim, I., DeCastro, A.,Desarrazin, C., Pharmaco Ther. 3:177-181. "Analgesic Effect of GradedDoses of Flurbiprofen in Postepisiotomy Pain".

Silberman found suprofen 200 mg more effective than aspirin 650 mg forpain relief in the treatment of moderate to severe pain resulting frommusculoskeletal pain. Silberman, H.M. "Multiple-Dose Comparison ofSuprofen, Aspirin and Placebo in the Treatment of Musculoskeletal Pain."Pharmacology 27:S 1, 65-73 (1983).

While these reported findings with respect to the outstanding analgesicproperties of the non-steroidal anti-inflammatory drugs comapred toaspirin or acetetaminophen have prompted the widespread acceptance andusage of these newer non-narcotic analgesics, as single entities, forthe treatment and management of acute and chronic inflammatory states,notably rheumatoid arthritis and osteoarthritis, the utilization ofthese agents in cough/cold compositions has not heretofore beenconsidered.

The non-steroidal anti-inflammatory drugs (NSAID's) for use in thepharmaceutical compositions and methods of use of the present inventionmay be selected from any of the following categories:

(1) The propionic acid derivatives;

(2) The acetic acid derivatives;

(3) The fenamic acid derivatives;

(4) The biphenylcarboxylic acid derivatives; and

(5) The oxicams.

Accordingly, the term "NSAID" as used herein is intended to mean anynon-narcotic analgesic non-steroidal anti-inflammatory compound,including the pharmaceutically acceptable non-toxic salts thereof,falling within one of the five structural categories above but excludingaspirin, acetaminophen and phenacetin.

The specific compounds falling within the foregoing definition of thenon-steroidal anti-inflammatory drugs for use in the present inventionare well known to those skilled in the art and reference may be had tovarious literature reference sources for their chemical structures,pharmacological activities, side effects, normal dosage ranges, etc.See, for example, Physician's Desk Reference, 35th Edition, 1981 and TheMerck Index, 9th Edition, Merck and Company, Rahway, New Jersey (1976)and Cutting's Handbook of Pharmacology, 6th Edition, Ed. T. Z. Czacky,M. D., Appleton-Century-Crofts, New York, 1979, Chapter 49:538-550.

Of the propionic acid derivatives for use herein, ibuprofen, naproxen,flurbiprofen, fenoprofen, ketoprofen, suprofen, fenbufen, and fluprofenmay be mentioned as particularly preferred compounds.

Of the acetic acid derivatives, presently preferred members includetolmetic sodium, zomepirac, sulindac and indomethacin.

Of the fenamic acid derivatives, particularly preferred compoundsinclude mefenamic acid and meclofenamate sodium.

The particularly preferred biphenylcarboxylic acid derivatives for usein the present invention include diflunisal and flufenisal.

The particularly advantageous oxicams include piroxicam, sudoxicam andisoxicam.

Of course, it will be appreciated by those skilled in the art, that anyof the foreoing compounds may be utilized in the form of theirpharmaceutically acceptable salt forms, e.g., --COO^('1) Na⁺, --COO⁻ K⁺,and the like.

Of the foregoing non-steroidal anti-inflammatory drugs, in the practiceof the preferred embodiment of the present invention, ibuprofen andnaproxen are most preferred.

With respect to the dosage amount of the non-steroidal anti-inflammatorydrugs in the compositions of the invention, although the specific dosewill vary depending upon the age and weight of the patient, the severityof the symptons, the incidence of side effects and the like, for humans,typical effective analgesic amounts of presently preferred NSAID's foruse in unit dose compositions of the invention are about 100-500 mgdiflunisal, about 25-100 mg zomepirac sodium, about 50-400 mg ibuprofen,most preferably 100-200 mg, about 125-500 mg naproxen, about 25-100 mgflurbiprofen, about 50-100 mg fenoprofen, about 10-20 mg piroxicam,about 125-250 mg mefenamic acid, about 100-400 mg fenbufen or about25-50 mg ketoprofen; however, greater or lesser amounts may be employedif desired or necessary. With respect to the compounds set forthhereinabove falling within the propionic acid derivative category,suitable dosage ranges for these compounds will generally fall withinthe range of 25 mg to 600 mg in each unit dose.

A complete description of the various NSAID's , including acceptableanalgesically effective amounts thereof for use in unit dosecompositions of the present invention also appears in applicantsco-pending U.S. application Ser. Nos. 474,358, filed Mar. 11, 1983, nowU.S. Pat. No. 4,486,436, and 578, 288, filed Feb. 8, 1984, now U.S. Pat.No. 4,522,826, the entire disclosures of which are incorporated hereinby reference.

The cough/cold pharmaceutical compositions of the present inventioncomprise, in addition to the non-steroidal anti-inflammatory drugs, atleast one active ingredient from the following pharmacological classes:antihistamines, sympathomimetics (decongestants), coughsuppressants-antitussives and expectorants. Typical therapeuticallyactive components from these categories, along with their usual adultdosage, for use in the pharmaceutical compositions and methods of theinvention are set forth in the following Table 1.

Among such Table 1 antihistamines, sympathomimetics, coughsuppressants-antitussives and expectorants, in combination with anon-steroidal anti-inflammatory drug, applicants have alreadydemonstrated a synergistically enhanced analgesic and anti-inflammatoryresponse in a mammalian organism. Again compare their copendingapplication, Ser. No. 578,288, filed Feb. 8, 1984, now U.S. Pat. No.4,522,826.

                                      TABLE I                                     __________________________________________________________________________                                     USUAL SINGLE                                 DRUG (FORM-SALT)                                                                              ACTION.sup.1                                                                        PREPARATIONS                                                                             DOSE (ADULT)                                 __________________________________________________________________________    chlorpheniramine (maleate)                                                                    A     Tablets, Capsules,                                                                         2-4 mg                                                           4 mg, 8 mg, 12 mg,                                                            (substained Action)                                                           12 mg                                                   brompheniramine (maleate)                                                                     A     Tablets, Capsules,                                                                         8-12 mg                                                          4 mg, 8 mg, 12 mg                                                             (Extentabs R)                                           dexchlorpheniramine (maleate)                                                                 A     Tablets,     2-6 mg                                                           2 mg, 4 mg, 6 mg,                                                             Syrup, Expectorant                                                            (2 mg/5 cc)                                             dexbrompheniramine (maleate)                                                                  A     Tablet, 6 mg                                                                             6 mg                                         triprolidine (HCl)                                                                            A     Tablet, 2.5 mg.                                                                          1.25-2.5 mg                                                        Syrup - 1.25 mg/5 cc                                    diphenhydramine (HCl)                                                                         A     Tablets, Capsules,                                                                       12.5-50 mg                                                         Elixir, Parenteral,                                                           25 mg, 50 mg                                                                  12.5 mg/5 cc; 10-50                                                           mg/ml.                                                  doxylamine (succinate)                                                                        A     Tablets, Elixir                                                                           7.5-10 mg                                                         10 mg, 7.5 mg/10 cc.,                                   tripelennamine (HCl)                                                                          A     Tablet, Elixir,                                                                            25-50 mg.                                                        25 mg, 50 mg,                                                                 37.5 mg/5 cc.                                           cyproheptadine (HCl)                                                                          A     Tablet, Syrup,                                                                           4 mg.                                                              4 mg, 1 mg/5 cc                                         carbinoxamine (maleate)                                                                       A     Syrup 4 mg/5 cc.,                                                                        4 mg.                                        bromodiphenhydramine (HCl)                                                                    A     Syrup      3.75 mg.                                                           3.75 mg/5 cc                                            phenindamine (tartrate)                                                                       A     Tablet, Elixir                                                                           10 mg.                                                             10 mg, 5 mg/5 cc.                                       pyrilamine (maleate, tannante)                                                                A     Tablet 12.5 mg.                                                                          12.5 mg.                                     azatadine (maleate)                                                                           A     Tablet, 1 mg.                                                                              1-2 mg.                                    pseudoephedrine (HCl)                                                                         D     Tablet, Capsule                                                                            60-120 mg.                                                       30 mg, 60 mg,                                                                 120 mg (sustained                                                             action)                                                 phenylpropanolamine (HCl)                                                                     D     Tablet, Capsule,                                                                           25-50 mg.                                                        Elixir, 25 mg, 50                                                             mg, 12.5 mg/5 cc                                        phenylephrine (bitartrate,                                                                    D     Tablet, Capsule                                                                            5-25 mg.                                   tannate, HBr, HCl)    Elixir,                                                                       5 mg, 10 mg, 25 mg,                                                           5 mg/5 cc.                                              caramiphen (edisylate)                                                                        CS    Capsule, Elixir                                                                            5-20 mg.                                                         20 mg,                                                                        5 mg/5 cc                                               dextromethorphan (HBr)                                                                        CS    Tablet, Capsule                                                                          30 mg.                                                             Elixir                                                                        15 mg. 30 mg.                                                                 15 mg/5 cc.                                             codeine (phosphate, sulfate)                                                                  CS    Tablet, Elixir                                                                           10 mg.                                                             10 mg,                                                                        10 mg/5 cc.                                             terpin hydrate  E     Tablet     300 mg.                                                            300 mg.                                                 guaifenesin (glyceryl guaiacolate)                                                            E     Tablet, Capsule                                                                          100 mg.                                                            Elixir, 100 mg,                                                               100 mg/5 cc.                                            potassium (Iodide citrate)                                                                    E     Tablet, Elixir,                                                                           150-300 mg.                                                       100 mg,                                                                       100 mg/5 cc.                                            potassium guaicolsulfonate                                                                    E     Elixir     80 mg                                                              80 mg/5 cc.                                             __________________________________________________________________________     .sup.1 A = antihistamine                                                      D = decongestant                                                              CS = cough suppressant                                                        E = expectorant                                                          

In the pharmaceutical compositions and methods of the present invention,the foregoing active ingredients will be combined with the non-steroidalanti-inflammatory drug(s) and will typically be administered inadmixture with suitable pharmaceutical diluents, excipients or carriers(collectively referred to herein as "carrier" materials) suitablyselected with respect to the intended form of administration, i.e., oraltablets, capsules, elixirs, syrups, etc. and consistent withconventional pharmaceutical practices. For instance, for oraladministration in the form of tablets or capsules, the active drugcomponents may be combined with any oral non-toxic pharmaceuticallyacceptable inert carrier such as lactose, starch, sucrose, cellulose,magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol,ethyl alcohol (liquid forms) and the like. Moreover, when desired ornecessary, suitable binders, lubricants, disintegrating agents andcoloring agents can also be incorporated in the mixture. Suitablebinders include starch, gelatin, natural sugars, corn sweeteners,natural and synthetic gums such as acacia, sodium alginate,carboxymethylcellulose, polyethylene glycol and waxes. Among thelubricants there may be mentioned for use in these dosage forms, boricacid, sodium benzoate, sodium acette, sodium chloride, etc.Disintegrators include, without limitation, starch, methylcellulose,agar, bentonite, guar gum, etc. Sweetening and flavoring agents andpreservatives can also be included where appropriate.

Of course, additionally, the compositions of the present invention maybe formulated in sustained release form to provide the rate controlledrelease of any one or more of the components to optimize the therapeuticeffects, i.e, analgesia, antihistaminic, etc. while minimizingundesirable side effects. Suitable dosage forms for sustained releaseinclude layered tablets containing layers of varying disintegrationrates or controlled release polymeric matrices impregnated with theactive components and shaped in tablet form or capsules containing suchimpregnated or encapsulated porous polymeric matrices.

As representative suitable formulations consistent with the objects,features and advantages of the present invention, the followingnon-limiting examples are provided.

EXAMPLE 1

Ibuprofen--200 mg

Chlorpheniramine maleate--8 mg

Phenylpropanolamine hydrochloride--8 mg

Dextromethorphan hydrobromide--30 mg

Guaifenesin--100 mg

Triturate active ingredients and q.s. with lactose to selected capsulesize.

EXAMPLE 2

In each fluid ounce:

Naproxen (sodium) 250 mg, dextromethorphan HB 30 mg, phenylpropanolaminehydrochloride 25 mg, orange flavoring and alcohol 10% v/v.

From the foreging, other typical acceptable pharmaceutical formulationswill be apparent to those skilled in the art of pharmaceuticalformulations.

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit of the invention. Forexample, effective dosages other than the preferred ranges set forthhereinabove with respect to the active ingredients may be applicable asa consequence of variations of the responsiveness of the mammal treated,severity of symptoms, dosage related adverse effects, if any, observedand similar considerations. Accordingly, such expected variations ordifferences in the practice of the present invention and the resultsobtained are contemplated in accordance with the objects and practicesof the present invention. It is intended, therefore that the inventionbe limited only by the scope of the claims which follow:

What is claimed is:
 1. A pharmaceutical composition of matter for use inthe treatment of cough, cold, cold-like and/or flu symptoms in amammalian organism, said composition comprising a sympathomimetically,analgesically and anti-inflammatorily effective amount of (i) at leastone of the acetic acid NSAIDs, tolmetin, zomepirac, sulindac,indomethacin, or pharmaceutically acceptable salt thereof, incombinatory immixture with (ii) at least one of the sympathomimeticamines, pseudoephedrine, phenylpropanolamine, phenylephrine, orpharmaceutically acceptable salt thereof.
 2. The pharmaceuticalcomposition as defined by claim 1, said NSAID (i) comprisingindomethacin or pharmaceutically acceptable salt thereof.
 3. Thepharmaceutical composition as defined by claim 1, said NSAID (i)comprising tolmetin or pharmaceutically acceptable salt thereof.
 4. Thepharmaceutical composition as defined by claim 1, said NSAID (i)comprising zomerpirac or pharmaceutically acceptable salt thereof. 5.The pharmaceutical composition as defined by claim 1, said NSAID (i)comprising sulindac or pharmaceutically acceptable salt thereof.
 6. Thepharmaceutical composition as defined by claim 1, comprising at least 25mg of said NSAID (i).
 7. The pharmaceutical composition as defined byclaim 6, comprising from 25 mg to 100 mg of said NSAID (i).
 8. Thepharmaceutical composition as defined by claim 1, comprising (ii) from60 mg to 120 mg of pseudoephedrine or pharmaceutically acceptable saltthereof.
 9. The pharmaceutical composition as defined by claim 1,comprising (ii) from 25 mg to 50 mg of phenylpropanolamine orpharmaceutically acceptable salt thereof.
 10. The pharmaceuticalcomposition as defined by claim 1, comprising (ii) from 5 mg to 25 mg ofphenylephrine or pharmaceutically acceptable salt thereof.
 11. Thepharmaceutical composition as defined by claim 1, further comprising(iii) a pharmaceutically acceptable non-toxic carrier.
 12. Thepharmaceutical composition as defined by claim 1, in oral dosage form.13. The pharmaceutical composition as defined by claim 12, said oraldosage form comprising a tablet.
 14. The pharmaceutical composition asdefined by claim 12, said oral dosage form comprising a capsule.
 15. Thepharamceutical composition as defined by claim 12, said oral dosage formcomprising an elixir.
 16. A method for the treatment of cough, cold,cold-like and/or flu symptoms in a mammalian organism in need of suchtreatment, comprising administering to such organism a symptomrelieving, sympathomimetically, analgesically and anti-inflammatorilyeffective amount of (i) at least one of the acetic acid NSAIDs,tolmetin, zomepirac, sulindac, indomethacin, or pharmaceuticallyacceptable salt thereof, in combinatory immixture with (ii) at least onesympathomimetic decongestant or bronchodilator, or pharmaceuticallyacceptable salt thereof.
 17. A method for the treatment of cough, cold,cold-like and/or flu symptoms in a mammalian organism in need of suchtreatment, comprising administering to such organism the pharmaceuticalcomposition as defined by claim
 1. 18. A method for the treatment ofcough, cold, cold-like and/or flu symptoms in a mammalian organism inneed of such treatment, comprising administering to such organism thepharmaceutical composition as defined by claim 11.